Project Summary The hypothalamic?pituitary?adrenal axis (HPA axis) figures prominently in the pathophysiology of stress- related disorders including depression, anxiety, post-traumatic stress disorder (PTSD), and addictive behaviors, neurological disorders such as Alzheimer's disease, as well as endocrine disorders such as obesity, diabetes, and anorexia. The enzyme 11?-hydroxysteroid dehydrogenase-1 (11?-HSD1) converts cortisone to cortisol, and thus controls a key pathway in the regulation of HPA axis function. The availability of PET imaging agents for 11?-HSD1 will provide non-invasive biomarkers to interrogate the enzyme in vivo in human subjects and gain insights into its function and dysfunction in the aforementioned disorders. Further, PET imaging with 11?-HSD1 radiotracers can be used as an in vivo biomarker to assess target engagement and correlate target occupancy, dose exposure and therapeutic response of 11?-HSD1 inhibitors current in clinical trials, thus aiding the development of novel therapeutic agents for these disorders. In this grant application, we propose to synthesize, evaluate and validate 18F-AS2471903 as an effective radiotracer for PET imaging studies of 11?-HSD1 in humans. We have carried out the synthesis and evaluation of 11C-AS2471907 in non-human primates and humans and demonstrated its usefulness as an effective radiotracer to image and quantify the expression of 11?-HSD1 in the brain, and to determine in humans the receptor occupancy of a 11?-HSD1 inhibitor currently under development as therapeutic agent for cognitive disorders. Further, we have prepared 18F-AS2471903 via innovative radiochemistry methodology and performed its initial assessment in non-human primates. In this project we propose to carry out a comprehensive evaluation of 18F-AS2471903 in rhesus monkeys and validate its radiosynthesis. Afterwards it will be translated to PET imaging studies in humans to quantify its regional specific binding signals, to assess the reproducibility of binding parameters and to determine the non-displaceable volume of distribution. Sex and age-related differences in the expression of 11?-HSD1 in the brain will also be investigated, and correlation of 11?-HSD1 expression with circulating cortisol levels, as well as anxiety and stress scores, will also be explored, to understand the expression of 11?-HSD1 under various physiological conditions. Our ultimate goal is to provide the PET imaging community with an effective radiotracer for in vivo imaging of 11?-HSD1 in humans. The development and successful deployment of effective PET imaging radiotracer for 11?-HSD1 will enable, for the first time, the in vivo investigation of this key enzyme in psychiatric and neurological conditions, addictive disorders, and metabolic disease.